ITMI20121576A1 - PROCEDURE FOR THE PREPARATION OF VILAZODONE - Google Patents

Description

Description of the patent for industrial invention entitled:

"PROCEDURE FOR THE PREPARATION OF VILAZODONE"

The invention relates to a method for the preparation of Vilazodone in an aqueous environment with the use of cheap inorganic bases such as sodium carbonate, sodium hydroxide, potassium carbonate and the like. The method provides high yields without the need for organic solvents.

Background of the invention

Vilazodone (hydrochloride), 5 (4- [4- (5-cyano-1 // - indol-3-yl) butyl)] piperazin-1-yl) benzofuran-2-carboxyamide (hydrochloride), is an inhibitor of reuptake of serotonin and a partial agonist of 5-HT1A receptors. Vilazodone is used as a drug for the treatment of severe depressive symptoms in adults.

The preparation of vilazodone hydrochloride was originally described, in a very generic way, in EP 648767. The synthesis scheme provides for the N-alkylation of the piperazine derivative II with the chlorobutyl indole I in acetonitrile to give the compound of formula III; the activation of the carboxyl group of compound III with 2-chloro-l-methylpyridinium methanesulfonate in N-methylpyrrolidone and subsequent treatment with gaseous ammonia leads to vilazodone, isolated as hydrochloride.

In the publication Journal of Medicinal Chemistry 47, 4684-4692 (2004) a similar sequence is described in detail, which includes the condensation between compounds of formula I and IV (used as hydrochloride) to give compound V. The reaction is carried out in acetonitrile hot in the presence of triethylamine and potassium carbonate. Compound V is then purified by silica chromatography and isolated as dihydrochloride. The reaction yield is modest (32%). Ester V is then hydrolyzed to give compound III and then converted into vilazodone and finally into vilazodone hydrochloride with yields of 80%, 72% and 79% respectively.

EP 1874762 claims two alternative processes for the synthesis of vilazodone,

the first for "coupling", catalyzed by palladium, of indolyl-butylpiperazine VI with 5-bromobenzofuran-2-carboxyamide VII and the second for reductive amination between piperazine-benzofuran-carboxyamide IX indolyl-butanal VIII with sodium cyanoborohydride in methanol.

Even if in the introductory part of the patent reference is made to global yields equal to or higher than those of the "prior art", no precise indications are given in the experimental part. In addition, the aforementioned processes have Γ disadvantage, the first of the removal of palladium and the second of the use of a reducing agent unsuitable for use on an industrial scale.

Description of the invention

Surprisingly we have found that vilazodone can be obtained in excellent yield and high purity by N-alkylation of piperazinbenzofuran-carboxyamide IX, or a salt thereof,

with indolyl-butyl derivative X,

X

where LG is halogen, such as chlorine, bromine or iodo, or a sulfonate group, such as methanesulfonate or toluenesulfonate.

Preferably LG is chlorine or methanesulfonate, more preferably LG is chlorine (compound of formula I).

The process of the invention is illustrated in the following diagram:

N-alkylation reactions such as that between the compounds of formula I and IX or their analogues (see for example, in addition to the previous references, WO 2004113325 and WO 2004113326) have so far been carried out using organic solvents, in the presence of acid acceptors, which in addition to presenting problems of disposal and potential toxicity (e.g. NMP, DMF, DMAC) they involve the formation of impurities, such as those deriving from the quaternization of piperidine nitrogen, with strong penalties of yields and quality.

The process of the invention instead provides for the alkylation of the compound of formula IX (or a salt thereof) with a derivative of formula X, preferably with the compound of formula I, in aqueous suspension in the presence of an inorganic base. Vilazodone is thus obtained in high yields, typically greater than 90%, and high purity, typically greater than 90%.

If a salt of compound IX is used, preferred salts are hydrochloride, hydrobromide and methanesulfonate.

The reaction can be carried out in water alone or in the presence of variable quantities of organic solvent such as for example methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile, toluene, methyltetrahydrofuran. Preferably the organic solvent, which can be used for the dissolution of IX or X, is present in a percentage lower than 20%. Even more preferably, only water is used as the reaction solvent.

The inorganic base is typically a bicarbonate, carbonate or phosphate of an alkali or alkaline earth metal. Preferably the inorganic base is soluble in water. Even more preferably the inorganic base is sodium or potassium carbonate.

The reaction can be carried out at a temperature between room temperature and the boiling temperature of the aqueous solution, preferably between 40 ° C and the boiling temperature of the aqueous solution, more preferably between 60 ° C and 90 ° C.

The reaction time is between 4 and 48 hours, more preferably between 8 and 24 hours.

If an organic solvent is also present, this can be removed, at the end of the reaction, in whole or in part by distillation or concentration under vacuum.

Typically the Vilazodone precipitates from the aqueous reaction solvent and is isolated by simple filtration of the reaction mixture cooled to room temperature. The solid is then washed with water or aqueous solvent and dried under vacuum.

The Vilazodone thus obtained can be further purified by crystallization.

Vilazodone can be converted into Vilazodone hydrochloride according to one of the known methods, for example by treatment with hydrochloric acid in isopropyl alcohol [Journal of Medicinal Chemistry 47, 4684-4692 (2004)].

The two starting materials of formula X and IX (IX both as a free base and as a salt) can be easily prepared by procedures known in the literature. For example, the preparation of chlorine derivative I (X with LG = Cl) starting from 5-cyanoindole XI is mentioned in EP 648767 and EP683166 and described in detail in Journal of Medicinal Chemistry 47, 4684-4692 (2004). The sequence involves radiation of 5-cyanoindole XI in position 3 with 4-chlorobutyryl chloride and subsequent reduction of ketone XII with sodium bis (2-methoxyethoxy) aluminum hydride. Alternatively (CN 102267932, CN 102267985) XII can be converted by treatment with sodium borohydride into hydroxy derivative XIII and then into a sulfonate of formula X (LG = OS02R) by treatment with a sulfonyl chloride in the presence of an organic base.

The preparation of piperazine-benzofuran-carboxyamide IX is described for example in EP 738722 and includes the conversion of ester XIV (PG = BOC) into amide XI and subsequent unblocking of the protective group (BOC: tert-butoxycarbonyl) on piperazine nitrogen , obtaining IX as the hydrochloride. Another process (WO 0140219) provides for the amination, catalyzed by transition metals, of the bromoderivative of formula VI with protected piperazine on a nitrogen atom (PG preferably benzyl or BOC) to give compound XV and, after removal of the protective group , compound IX; alternatively IX can be obtained directly by reaction of VI with piperazine. Another convenient process includes the reaction of the amino derivative XVI (easily obtainable by reducing the corresponding nitro derivative) with bis (2-chloroethyl) amine hydrochloride; better conditions for carrying out this type of reaction are reported in Tetrahedron Letters 46, 7921 (2005).

The process is now further illustrated by the following examples.

Example 1 - Synthesis of basic Vilazodone

In a suitable reactor, load 1.67 Kg of Sodium Carbonate and 10 1 of water. Then load 1.14 kg of chlorine derivative I.

Heat the mixture to 70 ° C and load 1.50 kg of intermediate IX as hydrochloride.

Bring the temperature to 95 ° C and shake for 12 hours.

Verify complete conversion via HPLC.

Cool to 70 ° C and filter the raw Vilazodone by washing with water. After drying, raw Vilazodone is obtained with purity> 90%. The crude Vilazodone is purified by crystallization from organic solvent with standard methods obtaining a product with purity> 99.5% Molar yield = 81%.

Example 2 - Synthesis of basic Vilazodone

Synthesis carried out under the same conditions reported in Example 1 using 2.18 Kg of Potassium Carbonate as a base.

Molar yield = 80%

Example 3 - Synthesis of Vilazodone hydrochloride

The preparation of Vilazodone hydrochloride was carried out according to the method described in detail in the "prior art" of patent application W002102794 (Merck) with reference to the procedure used for the preparation of Vilazodone hydrochloride mentioned in the experimental part of US patent 5532241 (Merck) .

In a special reactor, 10 g of basic Vilazodone are heat treated with 430 ml of isopropyl alcohol.

230 ml of a 0.1 M solution of HCl in isopropyl alcohol are dropped into the reactor in 10 minutes.

The suspension filters out. The product is dried at 25 ° C obtaining the polymorphic crystal described as Form IV in the aforementioned patent application W002102794 (identification by IR and XDR).

By drying the product at 90 ° C, the polymorphic crystal described as Form III in the same patent application is obtained.

Both crystalline forms exhibit a very high HPLC quality profile.

Claims (10)

CLAIMS 1. Process for the preparation of Vilazodone which includes the N-alkylation reaction of piperazine-benzofuran-carboxyamide, or one of its salt, of formula IX with the indolyl-butyl derivative of formula X, where LG is halogen or a sulfonate group. 2. Process according to claim 1 wherein LG is chlorine, methanesulfonate or toluenesulfonate. 3. Process according to claim 2 wherein LG is chlorine. 4. Process according to one or more of claims 1 to 3 wherein the N-alkylation is carried out in aqueous suspension in the presence of an inorganic base. 5. Process according to claim 4 in which the N-alkylation is carried out in water alone or in the presence of variable quantities of organic solvent, selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile, toluene, methyltetrahydrofuran. 6. Process according to claim 5 in which only water is used as the reaction solvent. Process according to one or more of claims 1 to 6 wherein the inorganic base is a bicarbonate, carbonate or phosphate of an alkali or alkaline earth metal. 8. Process according to claim 7 wherein the base is sodium or potassium carbonate. 9. Process according to one or more of claims 1 to 8 wherein the reaction is carried out at a temperature between room temperature and the boiling temperature of the aqueous solution. 10. Process according to claim 9 wherein the temperature is between 60 ° C and 90 ° C.