ITMI20120589A1 - USEFUL INTERMEDIATES FOR THE SYNTHESIS OF FEXOPHENADINE, PROCESS FOR THEIR PREPARATION AND FOR THE PREPARATION OF FEXOFENADINE - Google Patents

Description

â € Intermediates useful for the synthesis of Fexofenadine, a process for their preparation and for the preparation of Fexofenadineâ €

DESCRIPTION

The present invention relates to new intermediates useful for the synthesis of Fexofenadine, a process for their preparation and their transformation into Fexofenadine.

Fexofenadine is an oral antihistamine, so-called "second generation", with no side effects, used to treat the symptoms of allergic reactions, symptoms related to the release of histamine. Histamine is one of the chemical mediators of inflammation, resulting from the decarboxylation of histidine by histidine decarboxylase. Antihistamines inhibit the activity of histamine H1 receptors, present above all in the skin and bronchi, blocking the release of histamine. The contact of an allergen (substance capable of producing allergic manifestations) with the histamine H1 receptors stimulates the release of histamine, causing capillary dilation, capillary permeability and vasodilation, thus causing local erythema, local edema (swelling) and redness. With the release of histamine, itching can also occur and, in predisposed subjects, severe bronchoconstriction, gastrointestinal motility and an increase in secretion of the salivary and bronchial glands.

Fexofenadine is the corresponding carboxylic acid of Terfenadine, of which it is the main metabolite. However, Fexofenadine does not have the cardiotoxic effects of Terfenadine and, thanks to the fact that it does not pass the blood brain barrier, it does not cause the patient those discomforts typical of so-called â € œfirst generationâ € antihistamines, such as drowsiness and fatigue.

Fexofenadine is a compound of formula (I)

HOOC

No.

OH (I)

OH

chemically known as 2- [4 - [1-hydroxy-4 - [4 - (hydroxy-diphenylmethyl) - 1-piperidyl] butyl] phenyl] - 2-methyl-propanoic acid, described in US 4,254,129 and marketed under the trade name of Allegra <®>.

WO 02/10115 (Texcontor Etablissement) describes a process for the synthesis of Fexofenadine, which includes the reaction of the compound of formula (II)

H3COOC

(II) OH

with a compound based on copper or silver, in particular copper oxide (II) in the presence of palladium, or in a compound containing palladium, to give the intermediate of formula (III)

H3COOC

(III) OH

OR

CN 102079708 (Zhejiang Giming Pharmaceutical Co ltd) describes a process for the synthesis of Fexofenadine which includes the preparation of the compound of formula (IV)

H3COOC

(IV) Cl

OR

by reaction of the intermediate of formula (II) with a mercury compound (II), in particular mercury oxide (II).

Both processes are characterized by the use of expensive and difficult to handle reagents, as they are very toxic by inhalation, skin contact and ingestion, as well as very harmful at an environmental level.

We have now found new compounds, which have proved to be useful intermediates for the synthesis of Fexofenadine which do not involve the use of toxic reagents such as mercury-based or expensive salts such as palladium-based salts and which allow for easy-to-use reaction conditions. conduct and low environmental impact.

Therefore, the object of the present invention is a process for the synthesis of the compound of formula (VI) starting from the compound of formula (IIa) according to scheme 1

(IIa)

(VI) Scheme 1

where R1 represents a linear or branched C1-C20 alkyl group and R4 represents a halogen or a hydroxyl group, by reaction with hydrobromic acid in acetic acid, at a temperature between 30 ° C and 50 ° C. The compound of formula (VI) can be converted into Fexofenadine according to the techniques reported in the patent application MI2012A000329 in the name of the Applicant.

A preferred embodiment of the process object of the present invention is the synthesis of the compound of formula (VIa) starting from compound (II) according to scheme 2

H3COOC

(II) OH

H3COOC (VIa) Br

OR

Scheme 2

by reaction with hydrobromic acid in acetic acid, at a temperature between 30 ° C and 50 ° C.

A further object of the present invention is constituted by a process for the synthesis of Fexofenadine, starting from intermediates of formula (VI), which includes

a) the transformation of compound (VI) into compound (Vc)

R1OOC

(Vc)

Br

R5O OR6

where R1, R5 and R6 the same or different from each other, represent linear or branched C1-C20alkyl groups, by reaction with a trialkylorthoformate, in an alcoholic solvent, in the presence of an acid catalyst, at a temperature between 25 ° C and the reflux temperature of the solvent,

b) the transformation of the compound (Vc) by reaction with azaciclonol in a suitable solvent in the presence of a base at a temperature between 20 ° C and the reflux temperature of the solvent followed by the eventual saponification and any subsequent treatment with acetic acid to give the compound of formula (VII)

R1OOC

(VII)

No.

R5O OR6

OH

where R1 represents hydrogen or a linear or branched C1-C20alkyl group and R5e R6 the same or different from each other, represent linear or branched C1-C20alkyl groups;

c) the deacetalization of compound (VII) by reaction with a strong aqueous acid in the presence of a suitable solvent at a temperature between 20 ° C and 40 ° C to give the compound of formula (VIII)

R1OOC

(VIII)

No.

OR

OH

where R1 represents hydrogen or a linear or branched C1-C20alkyl group

d) the transformation of compound (VIII) to Fexofenadine.

Step d) of the process object of the present invention is known and described in the literature in patent application WO 2011/158262 in the name of the Applicant.

If the saponification reaction is not carried out in step b) of the process object of the present invention, said reaction can be carried out in one of the following steps c) and d). The saponification reaction is carried out according to the techniques known in the art, preferably in the presence of sodium hydroxide or potassium hydroxide in methanol.

In the process object of the present invention, in step a) the trialkylorthoformate used is selected from trimethylorthoformate, triethylorthoformate or triisopropylorthoformate. Trimethylorthoformate is preferably used.

In step a), the alcoholic solvent used is a linear or branched C1-C4 compound preferably selected from methanol, ethanol, isopropanol, butanol. Methanol is preferably used.

In step a) of the process object of the present invention, the acid catalyst is preferably selected from sulfuric acid, camphorsulfonic acid and methanesulfonic acid. Camphorsulfonic acid is preferably used.

Preferably in step b) of the process object of the present invention, the solvent used is selected from toluene, acetonitrile, tetrahydrofuran. Preferably toluene is used.

In step b) of the process object of the present invention, the base used is preferably chosen from sodium bicarbonate, potassium carbonate, triethylamine. Preferably sodium bicarbonate is used.

In step b) of the process object of the present invention the possible saponification reaction is carried out according to techniques known in the art, preferably in the presence of sodium hydroxide or potassium hydroxide in methanol.

Preferably in step c) of the process object of the present invention, the aqueous strong acid used is selected from sulfuric acid, hydrochloric acid.

In step c) of the process object of the present invention, the solvent is preferably selected from methanol, ethanol, isopropanol. Methanol is preferably used.

In a preferred embodiment, the process for the synthesis of Fexofenadine, object of the present invention, starts from intermediates of formula (VIa), and comprises:

e) the transformation of compound (VIa) into compound (Vd)

H3COOC

(Vd)

Br

H3CO OCH3

by reaction with trimethylorthoformate, in an alcoholic solvent, in the presence of an acid catalyst, at a temperature between 25 ° C and the reflux temperature of the solvent,

f) the transformation of the compound of formula (Vd) by reaction with azaciclonol in a suitable solvent in the presence of a base at the temperature between 20 ° C and the reflux temperature of the solvent to give a compound of formula (VIIa)

H3COOC

N (VIIa)

H3CO OCH3

OH

g) saponification of the compound of formula (VIIa) with a base in linear or branched C1-C4 alcoholic solvent and subsequent treatment with acetic acid to give the compound of formula (VIIc)

HOOC

(VIIc)

No.

H3CO OCH3

OH

h) the deacetalization of the compound of formula (VIIc) by treatment with an aqueous strong acid in a linear or branched C1-C4 alcoholic solvent, at a temperature between 20 ° C and 40 ° C; i) the transformation of the compound obtained into Fexofenadine.

In step e), the alcoholic solvent used is a linear or branched C1-C4 compound preferably selected from methanol, ethanol, isopropanol, butanol. Methanol is preferably used.

In step e) of the process object of the present invention, the acid catalyst is preferably selected from sulfuric acid, camphorsulfonic acid and methanesulfonic acid. Camphorsulfonic acid is preferably used.

Preferably in step f) of the process object of the present invention, the solvent used is selected from toluene, acetonitrile, tetrahydrofuran. Preferably toluene is used.

In step f) of the process object of the present invention, the base used is preferably chosen from sodium bicarbonate, potassium carbonate, triethylamine. Preferably sodium bicarbonate is used.

Preferably in step g) of the process object of the present invention, the solvent is selected from methanol, ethanol, isopropanol. Methanol is preferably used.

In step g) of the process object of the present invention, the base used is preferably selected between sodium hydroxide and potassium hydroxide. In step h) the alcoholic solvent used is preferably selected from methanol, ethanol, isopropanol. Methanol is preferably used.

Preferably in step h) of the process object of the present invention the aqueous strong acid used is selected from hydrochloric acid, sulfuric acid. Hydrochloric acid is preferably used.

The compound of formula (VIIc) is new and therefore constitutes a further object of the present invention.

All the terms used in the present application, unless otherwise indicated, must be understood in their common meaning as known in the art. Other more specific definitions for some terms, as used in this question, are highlighted below and apply consistently throughout the description and claims, unless a different definition explicitly provides a broader definition.

The term â € œalkylâ € refers to a branched or linear hydrocarbon, containing from 1 to 20 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc. A preferred alkyl group of the present invention is n-butyl.

Although the present invention has been described in its characteristic aspects, modifications and equivalents which are apparent to one skilled in the art are included in the present invention.

Hereinafter, the present invention will be illustrated by means of some examples, which are not to be seen as limiting the scope of the invention.

EXAMPLES

EXAMPLE 1

Preparation of methyl 4- (4-bromo-1-oxybutyl) -Î ±, Î ± -dimethylphenylacetate (compound VIa)

20 g of hydrobromic acid 33% in acetic acid (0.082 mol) and 10 g of methyl 2- (4- (4-hydroxybut-1-inyl) -2-methyl propanoate (0.04 mol), maintaining the temperature at 35 ° C and the reaction mixture was maintained under these conditions for four hours. At the end of the reaction, the temperature was brought to 20 ° C, 50 ml of toluene were added and the organic phase was washed with water (3 x 25 ml). The combined organic phases were concentrated to residue by vacuum distillation to give 10.6 g of methyl 4- (4-bromo-1-oxybutyl) -Î ±, Î ± dimethylphenylacetate.

<1> H-NMR (CDCl3, 300 MHz): Î ́ 7.96 (d, 2H), 7.42 (d, 2H), 3.58 (s, 3H), 3.54 (t, 2H) , 3.17 (t, 2H), 2.99 (m, 2H), 1.58 (s, 6H).

EXAMPLE 2

Preparation of 2- (4- (4- (4- (hydroxydiphenylmethyl) piperidin-1-yl) -1,1-dimethoxybutyl) phenyl) -2-methylpropanoic acid (compound VIIc)

102 g of methyl 2- (4- (4- (4- (hydroxydiphenylmethyl) piperidin-1-yl) -1,1-dimethoxybutyl) phenyl) -2-methylpropanoate (0.18 mol ), 270 ml of methanol and 40.8 g of sodium hydroxide solution at 30% (0.31 mol), the reaction mixture was brought to the reflux temperature of the solvent and maintained under these conditions for four hours. At the end of the reaction, the temperature was brought to 20 ° C and 18.4 g of glacial acetic acid (0.31 mol) were added. The precipitated solid was filtered and washed with methanol (2 x 30 ml) and dried in a vacuum oven at 40 ° C until constant weight, to give 80 g of 2- (4- (4- (4- (hydroxydiphenylmethyl ) piperidin-1-yl) -1,1-dimethoxybutyl) phenyl) -2-methylpropanoic.

<1> H-NMR (DMSO, 300 MHz): Î ́ 7.48 (d, 4H), 7.31 (s, 4H), 7.23 (m, 4H), 7.10 (m, 2H) , 3.02 (s, 6H), 2.60 (d, 2H), 2.40 (m, 1H), 2.03 (m, 2H), 1.77 (m, 4H), 1.42 ( s, 6H), 1.36 (m, 2H), 1.68 (m, 2H), 0.99 (m, 2H).

EXAMPLE 3

Preparation of Fexofenadine

10 g of 2- (4- (4- (4- (hydroxydiphenylmethyl) piperidin-1-yl) -1,1-dimethoxybutyl) phenyl) -2-methylpropanoic acid (0.018 mol) were charged into a reaction flask, 30 ml of methanol and 2 g of hydrochloric acid solution at 37% (0.018 mol), the reaction mixture was brought to a temperature of 25 ° C and kept under these conditions for one hour. At the end of the reaction, 5 g of sodium hydroxide solution at 30% (0.038 mol) and 0.4 g of sodium boron hydride (0.010 mol) were introduced, the temperature was brought to 40 ° C and the reaction mixture à It was kept in these conditions for ten hours. At the end of the reaction, the temperature was brought to 15 ° C and 1.2 g of acetic acid (0.02 mol) and 10 ml of water were added. The suspension is filtered and the solid is washed with a 1: 1 water / methanol mixture (2 x 4 ml). The solid is dried under vacuum at 40 ° C and 9 g of Fexofenadine are obtained.

Claims (8)

CLAIMS 1) A process for the synthesis of the compound of formula (VI) starting from the compound of formula (IIa) according to the scheme (IIa) (YOU) where R1 represents a linear or branched C1-C20 alkyl group and R4 represents a halogen or a hydroxyl group, by reaction with hydrobromic acid in acetic acid, at a temperature between 30 ° C and 50 ° C. 2) A process according to claim 1, in which R1 represents a methyl group and R4 represents a hydroxyl group. 3) A process for the synthesis of Fexofenadine, which includes a) the transformation of compound (VI) into compound (Vc) R1OOC (Vc) Br R5O OR6 where R1, R5 and R6 the same or different from each other, represent linear or branched C1-C20alkyl groups, by reaction with a trialkylorthoformate, in an alcoholic solvent, in the presence of an acid catalyst, at a temperature between 25 ° C and the reflux temperature of the solvent, b) the transformation of the compound (Vc) by reaction with azaciclonol in a suitable solvent in the presence of a base at a temperature between 20 ° C and the return temperature of the solvent followed by the eventual saponification and any subsequent treatment with acid acetic to give the compound of formula (VII) R1OOC N (VII) R5O OR6 OH where R1 represents hydrogen or a linear or branched C1-C20alkyl group and R5e R6 the same or different from each other, represent linear or branched C1-C20alkyl groups, c) the deacetalization of compound (VII) by reaction with a strong aqueous acid in the presence of a suitable solvent at a temperature between 20 ° C and 40 ° C to give the compound of formula (VIII) R1OOC (VIII) No. OR OH where R1 represents hydrogen or a linear or branched C1-C20alkyl group d) the transformation of compound (VIII) to Fexofenadine. 4) A process according to claim 3, wherein step b) comprises the saponification reaction and subsequent treatment with acetic acid. 5) A process according to claim 3, which comprises e) the transformation of the compound (VIa) H3COOC (Street) Br OR in the compound (Vd) H3COOC (Vd) Br H3CO OCH3 by reaction with trimethylorthoformate, in an alcoholic solvent, in the presence of an acid catalyst, at a temperature between 25 ° C and the reflux temperature of the solvent, f) the transformation of the compound of formula (Vd) by reaction with azaciclonol in a suitable solvent in the presence of a base at the temperature between 20 ° C and the reflux temperature of the solvent to give a compound of formula (VIIa) H3COOC N (VIIa) H3CO OCH3 OH g) saponification of the compound of formula (VIIa) with a base in linear or branched C1-C4 alcoholic solvent and subsequent treatment with acetic acid to give the compound of formula (VIIc) HOOC (VIIc) No. H3CO OCH3 OH h) the deacetalization of the compound of formula (VIIc) by treatment with an aqueous strong acid in a linear or branched C1-C4 alcoholic solvent at a temperature between 20 ° C and 40 ° C; i) the transformation of the obtained compound into Fexofenadine. 6) A process according to claims 3 and 4 in which in step a) the trialkylorthoformate used is selected from trimethylorthoformate, triethylorthoformate or triisopropylorthoformate, preferably trimethylorthoformate, the alcoholic solvent used is selected from methanol, ethanol, isopropanol, butanol, preferably and the acid catalyst is selected from sulfuric acid, camphorsulfonic acid and methanesulfonic acid, preferably camphorsulfonic acid; in step b) the solvent used is selected from toluene, acetonitrile, tetrahydrofuran, preferably toluene and the base is selected from sodium bicarbonate, potassium carbonate, triethylamine, preferably sodium bicarbonate; in step c) the aqueous strong acid is selected from sulfuric acid, hydrochloric acid and the solvent is preferably selected from methanol, ethanol, isopropanol, preferably methanol. 7) A process according to claim 5 wherein in step e) the alcoholic solvent is selected from methanol, ethanol, isopropanol, butanol, preferably methanol and the acid catalyst is selected from sulfuric acid, camphorsulfonic acid and methanesulfonic acid, preferably camphorsulfonic acid in step f) the solvent is selected from toluene, acetonitrile, tetrahydrofuran, preferably toluene and the base is selected from sodium bicarbonate, potassium carbonate, triethylamine, preferably sodium bicarbonate; in step g) the solvent is selected from methanol, ethanol, isopropanol, preferably methanol and the base is chosen from sodium hydroxide or potassium hydroxide; in step h) the alcoholic solvent used is selected from methanol, ethanol, isopropanol, preferably methanol and the strong aqueous acid is selected from hydrochloric acid, sulfuric acid, preferably hydrochloric acid. 8) The compound of formula (VIIc).